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The development of NASH-HCC prevention targeting EGFR

Research Project

Project/Area Number 19K08377
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

Umemura Atsushi  京都府立医科大学, 医学(系)研究科(研究院), 教授 (30759585)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
KeywordsEGFR / 肝癌 / 慢性肝障害 / Glucocorticoid receptor / ERRFI1 / MIG6 / NASH / ホノキオール / 肝発癌 / 慢性肝障 / HCC
Outline of Research at the Start

本研究は肝癌の原因として重要で、かつ現在世界的に増加中のNASHについて、その病態解明を通じて発癌予防法を開発することを目的とする。ほぼすべての肝癌は慢性肝疾患から発症するため、本検討では背景肝、つまり線維化進展や肝硬変に着目して解析することにより、新規アプローチによる発癌予防法の開発を目指す。特に背景肝におけるEGFRの活性化が発癌イニシエーションに関わることに初めて着目した検討であり、天然化合物によるEGFR抑制という新規アプローチにより、NASHに対する発癌予防法の確立を目標とする。

Outline of Final Research Achievements

Since EGFR signaling, a representative cancer signal, is activated in chronic liver injury, we searched for a method to prevent hepatocarcinogenesis by targeting EGFR. First, we focused on honokiol (HNK), which has been reported to have anticancer activity, and found that administration of HNK to NASH hepatocellular carcinoma (HCC) mice resulted in marked inhibition of carcinogenesis. Furthermore, analysis of human liver samples showed that GR-MIG6 was decreased and EGFR signaling was promoted in advanced NASH and HCC cases, and that HNK could activate GR-MIG6 in these cases. In addition, we found that HNK can inhibit fibrosis progression in the liver. We believe that we have obtained knowledge that can contribute to clinical practice in terms of drug repositioning.

Academic Significance and Societal Importance of the Research Achievements

肝癌は一度発症すると、再発を繰り返す難治性で予後不良の代表疾患である。正常肝から発症することはまれであり、ウイルス性肝疾患や脂肪肝などが進行し、肝硬変を代表とする線維化の進行した状態から肝発癌することが一般的である。本研究は、癌シグナルとしてよく知られるEGFRシグナルが、NASH肝で線維化が進行するとともに活性化する可能性、ならびに漢方薬として内服することができる天然化合物ホノキオールが肝癌のみならず、背景肝にも効果を発揮することでNASH肝癌の治療ならびに発癌予防に繋がる可能性を示したことで、学術的のみならず、社会的意義も大きいと考えられる。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (8 results)

All 2021 2020 2019 Other

All Int'l Joint Research (2 results) Journal Article (3 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (3 results)

  • [Int'l Joint Research] Universiity of California, San Diego(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] University of California, San Diego/Emory University(米国)

    • Related Report
      2020 Research-status Report
  • [Journal Article] Honokiol Acts as a Potent Anti-Fibrotic Agent in the Liver through Inhibition of TGF-β1/SMAD Signaling and Autophagy in Hepatic Stellate Cells.2021

    • Author(s)
      Kataoka S, Umemura A, Okuda K, Taketani H, Seko Y, Nishikawa T, Yamaguchi K, Moriguchi M, Kanbara Y, Arbiser JL, Shima T, Okanoue T, Itoh Y.
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 24 Pages: 13354-13354

    • DOI

      10.3390/ijms222413354

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress.2021

    • Author(s)
      Okuda K, Umemura A, Kataoka S, Yano K, Takahashi A, Okishio S, Taketani H, Seko Y, Nishikawa T, Yamaguchi K, Moriguchi M, Nakagawa H, Liu Y, Mitsumoto Y, Kanbara Y, Shima T, Okanoue T, Itoh Y.
    • Journal Title

      Frontiers in Oncology

      Volume: 11 Pages: 758549-758549

    • DOI

      10.3389/fonc.2021.758549

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor?MIG6 Axis2021

    • Author(s)
      Okuda Keiichiro、Umemura Atsushi、Umemura Shiori、Kataoka Seita、Taketani Hiroyoshi、Seko Yuya、Nishikawa Taichiro、Yamaguchi Kanji、Moriguchi Michihisa、Kanbara Yoshihiro、Arbiser Jack L.、Shima Toshihide、Okanoue Takeshi、Karin Michael、Itoh Yoshito
    • Journal Title

      Cancers

      Volume: 13 Issue: 7 Pages: 1515-1515

    • DOI

      10.3390/cancers13071515

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] グルタミン代謝は肝線維化および肝癌の治療・予防標的になり得る2021

    • Author(s)
      楳村敦詩
    • Organizer
      第107回消化器病学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 治療・予防法の確立を目指したNASH背景肝における発癌機構の解明2020

    • Author(s)
      楳村 敦詩
    • Organizer
      第56回日本肝臓学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] EGFRをターゲットとしたNASH発癌予防法の探求2019

    • Author(s)
      楳村 敦詩
    • Organizer
      第55回日本肝臓学会総会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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